Nerve signal conduction velocity or nerve conduction velocity (NCV) is a characteristic of all nerve signal transmission. NCV is the rate at which a nerve impulse (signal) travels along a nerve or nerve fiber. It is typically measured in meters per second (m/s).
Impaired NCV is a common result of nerve damage. NCV is frequently involved in neuropathies, including, for example, peripheral neuropathies, carpel tunnel syndrome, ulnar neuropathy, Guillain-Barré Syndrome, facioscapulohumeral muscular dystrophy and spinal disc herneation. Impaired nerve conduction velocity can result in diminished reflex responses and altered peripheral sensation including paresthesia and in some cases pain.
Measurement of nerve conduction velocity in peripheral nerves has long been a valuable diagnostic tool in orthopedic surgery, neurology and other branches of medicine. A diminished velocity, amplitude or abnormal wave form suggests nerve damage. Such studies may also be used to indicate the development or onset of an abnormal condition. Such studies could, therefore, be used to permit prophylactic corrective action to be undertaken before permanent damage to the nerve occurs.
While there is no necessity to treat transient impairment of nerve conduction velocity, acute or chronic impairment may require treatment. At the present time, the symptoms of impairment are treated by attempting to determine the cause of the impairment and if there is treatment available, treating the cause. However, in some diseases or disorders, such as some neuropathies, no treatment may be available for treating underlying diseases or disorders.
Treatment to improve NCV or amelioration of its symptoms is desirable and can help prevent further nerve degeneration or further complicating conditions. For example, in diabetic patients, foot ischemia and infection are serious and even life-threatening occurrences. The most common causal pathway to diabetic foot ulceration has been identified as the combination of neuropathy (sensory loss), deformity (for example, prominent metatarsal heads), and trauma (for example, that caused by ill-fitting footwear). Peripheral neuropathy coupled with impaired sensation make the foot susceptible to trauma, ulceration, and infection. Diabetic neuropathy impairs the nerve axon reflex that depends on healthy C-fiber nociceptor function. This neuropathic condition also further compromises the vasodilatory response present in conditions of stress, such as injury or inflammation, in the diabetic neuropathic foot. This impairment may partially explain why some ulcers in the diabetic neuropathic foot are either slow to heal or fail to heal at all, despite successful lower-extremity revascularization. Clearly, a treatment that improves NCV can ameliorate the neuropathic conditions that are causal in the development of pernicious injury. Yet, despite the central role neuropathy may play in the development of pernicious debilitating conditions, neuropathy is one of the most difficult conditions to treat.
Angiotensin II type 1 (AT1) receptor antagonists have been found to reverse impaired nerve conduction velocity in diabetic rats (WO 93/20816). Unfortunately, AT1 receptor antagonists are known to have other biological effects, particularly as antihypertensive agents. Treatment of impaired NCV with AT1 receptor antagonists can therefore precipitate undesirable or even proscriptive side effects. There is a need for other, more selective, or alternative treatments for impaired nerve conduction velocity that do not carry with them other biological effects.
Recently selective AT2 receptor antagonists have been found to have analgesic effects in the treatment of neuropathic pain (WO 2006/066361), particularly in painful diabetic neuropathy (PDN). But not all neuropathic conditions that are associated with impaired nerve conduction velocity result in neuropathic pain. In some cases, the first symptom of a neuropathic condition is paresthesia, which may or may not be associated with pain. Further, techniques of NCV measurement now facilitate the early detection of impaired or sub-optimal nerve signal conduction velocities prior to the onset of more pernicious symptoms and conditions. There is therefore a need in some subjects to improve or increase nerve conduction velocities as a result of early diagnosis of impaired NCV.
Surprisingly, the present inventors have discovered that administration of selective AT2 receptor antagonists can improve or increase nerve conduction velocities. Indeed, AT2 receptor antagonists can be used to restore impaired nerve conduction velocity to normal levels, which can lead to relief of symptoms such as diminished reflex responses and altered peripheral sensation, including paresthesia, and the prevention of further nerve damage, which may prevent the development of neuropathic pain and further impairments arising from impaired nerve conduction velocities.